Ezetimibe (Zetia)

Introduction

A new lipid lowering agent, ezetimibe (Zetia; Merck/Schering
Plough Pharmaceuticals), was recently approved by the Food and Drug Administration
(FDA). It is indicated as 1) monotherapy or in combination with HMG-CoA
Reductase Inhibitors (statins) for primary hypercholesterolemia, 2) for
homozygous sitosterolemia, and 3) in combination with atorvastatin (Lipitor®)
or simvastatin (Zocor®) for homozygous familial hypercholesterolemia.
Ezetimibe has a unique mechanism of action compared to other classes of
lipid-lowering agents. It inhibits the absorption of dietary and biliary
cholesterol decreasing the intestinal absorption by 54%. Ezetimibe does
not, however, affect triglyceride absorption.

The recent
cholesterol lowering guidelines, published by the National Cholesterol
Education Program Adult Treatment Panel III (NCEP ATP III), have low-density
lipoprotein (LDL) goals lower than previously recommended (See Table
1). Reaching these new goals may be difficult in some patients when
using the existing lipid-lowering agents; therefore, combination therapy
may be needed.

Statins are currently recommended as part of the management for hypercholesterolemia.
Combining statins with other available lipid-lowering drugs (e.g., fibrates,
niacin, and bile acid sequestrants) to reach target goals, may lead to
an increase in adverse effects or intolerable side effects. Now, however,
ezetimibe is a safe and effective alternative that may be used alone or
in combination with statins to reduce LDL levels to the recommended goal.

Table 1. NCEP ATP III Guidelines

Risk Category*

LDL goal(mg/dL)

Initiate TLCs (mg/dL)

Consider drug therapy (mg/dL)

CHD
or CHD equivalents

<100

>100

> 130

2+
Risk factors

<130

> 130

10
year risk 10-20% > 130

0-1
Risk factor

<160

> 160

> 190

Adapted from: Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol
in Adults. Executive Summary of the Third Report of the National Cholesterol
Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment
of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA
2001: 285(19); 2486-2536
CHD= Coronary Heart Disease
* Risk factors are described in the NCEP ATP III guidelines and consider
age, smoking status, family history and HDL level.Therapeutic Lifestyle Changes (TLC) as described in the NCEP
ATP-III guidelines
Risk determined by Framingham scoring

Pharmacology and Pharmacokinetics

Bile acid sequestrants (e.g., cholestyramine)
bind bile acids inhibiting their reabsorbtion. In turn, to produce more
bile acids, the liver breaks down cholesterol. Similar to bile acid sequestrants,
ezetimibe also acts in the small intestine. After oral administration,
it is glucuronidated to an active metabolite (ezetimibe glucuronide),
travels through the portal vessels to the bile, and is then brought back
to the small intestine via enterohepatic recycling. When food is ingested,
ezetimibe is excreted with the bile and acts at the brush border of the
small intestine to inhibit the uptake of dietary and biliary cholesterol
into the enterocytes. Furthermore, there is no inhibition of cholesterol
synthesis in the liver or increase in bile acid secretion.

The exact half-life of ezetimibe has yet to be determined; however, in the product
labeling, the half-life of both ezetimibe and its active metabolite is
listed as approximately 22 hours. It is excreted primarily in the feces
(78%). Due to unknown effects of increased exposure, ezetimibe is not
recommended in patients with moderate-to-severe hepatic insufficiency.
Currently, no dosage adjustment is necessary in renal insufficiency.

Selected Clinical Trials

Sudhop and colleagues conducted a randomized,
double-blind, placebo-controlled, 2-period, crossover trial evaluating
ezetimibe monotherapy (Circulation 2002;106:1943-8). Clinic patients
(n=18) with mild-to-moderate hypercholesterolemia were administered placebo
for a 2-week run-in period. Then, the patients were randomized to treatment
group 1 or 2. Treatment group 1 received ezetimibe 10 mg daily for 2 weeks,
followed by a 2-week washout period, and then received placebo for 2 weeks.
Treatment group 2 received placebo for 2 weeks, followed by a 2-week washout
period, and then received ezetimibe 10 mg daily for 2 weeks. The primary
efficacy endpoint was the effect of ezetimibe on the intestinal absorption
of cholesterol. Secondary endpoints included cholesterol synthesis, sterol
excretion, and plasma concentrations of cholesterol and non-cholesterol
sterols. Inclusion criteria for the trial were the following: 18 to 55
years of age, body mass index (BMI) between 19 and 30 kg/m2,
LDL cholesterol concentrations > 130 mg/dL but < 180mg/dL,
triglyceride (TG) concentrations below 250 mg/dL, and dietary cholesterol
intake between 200 and 500 mg/day. Patients were excluded from the study
if they received lipid-lowering drugs within 6 weeks of study entry, had
a history of excessive alcohol intake, had diabetes or other endocrine
disorders, had a history of hepatic disease, or gastrointestinal tract
dysfunction or renal dysfunction.

Of the 18 patients enrolled, all participants were male with a mean age
of 25.8 years (range: 24 to 58 years) and a mean body weight of 85 kg
(range: 66 to 105 kg). For the primary efficacy endpoint, ezetimibe decreased
intestinal cholesterol absorption by 54% (p<0.001). A compensatory
increase in cholesterol synthesis of 89% was found to be significant with
ezetimibe (1763 mg/day ± 1098) compared to placebo (931 mg/day
± 1027; p<0.001). After 2 weeks of receiving ezetimibe, the
mean percent change from baseline in all patients for LDL (baseline mean:
142 mg/dL) and total cholesterol (baseline mean: 220 mg/dL) was -20.4%
and -15.1%, respectively (p<0.001). Comparing ezetimibe to placebo
after the 2-week period, there was a -22.3% change in LDL as well as a
-13.2% change in total cholesterol (p<0.001). However, there was not
a significant change in high-density lipoprotein (HDL) or triglycerides
for ezetimibe as compared to placebo at the end of the 2-week period.
Ezetimibe therapy was well tolerated with no serious adverse effects or
critical laboratory elevations during treatment. In addition, there were
no elevations of aspartate or alanine aminotranferase (AST and ALT) of
three times greater than the upper limit of normal, and there were no
elevations of creatinine phosphokinase (CPK) 10 times the upper limit
of normal. The authors concluded that ezetimibe monotherapy in patients
with mild-to-moderate hypercholesteremia is effective in reducing the
intestinal absorption of cholesterol by 54%. Reductions in the total cholesterol
and LDL concentrations were also associated with ezetimibe treatment.

In the Journal of the American College of Cardiology, Davidson and colleagues
published a multicenter, placebo-controlled study evaluating the use of
ezetimibe in combination with simvastatin in patients (n= 668) with primary
hypercholesterolemia. The design of the trial was a 2 X 5 factorial which
consisted of a 2- to 12-week pre-treatment washout phase, a 4-week lead-in
placebo phase, and a 12-week treatment phase.

The treatment groups were the following: 1) ezetimibe 10 mg monotherapy, 2) ezetimibe
10 mg in combination with simvastatin 10-, 20-, 40- or 80-mg, 3) simvastatin
10-, 20-, 40- or 80-mg monotherapy, and 4) placebo. The objective of the
trial was to determine if the co-administration of ezetimibe and simvastatin
(pooled doses, n= 274) produced incremental reductions in LDL while maintaining
a safety profile similar to simvastatin monotherapy (pooled doses, n=263).
Secondary objectives were to evaluate changes in other lipid profile variables.
Patients were included if they were at least 18 years of age and had primary
hypercholesterolemia (defined as LDL > 145 mg/dL but £250
mg/dL) as well as TG < 350 mg/dL. Patients were excluded if
they exhibited congestive heart failure, uncontrolled cardiac arrhythmias,
history of unstable or severe peripheral artery disease within 3 months
of study entry, unstable angina pectoris, myocardial infarction, coronary
bypass surgery or angioplasty within six months of study entry, uncontrolled
or newly diagnosed diabetes mellitus, active or chronic hepatic or hepatobiliary
disease, known impairment of renal function, known coagulopathy or unstable
endocrine disease. Study results were based on an intent-to-treat analysis.
For the primary objective, when added to simvastatin, ezetimibe improved
LDL significantly compared to simvastatin monotherapy. More specifically,
the co-administration of ezetimibe and simvastatin (mean baseline direct
LDL: 176.3 mg/dL) and the use of simvastatin monotherapy (mean baseline
in direct LDL: 178.5 mg/dL) had a mean change in direct LDL of -49.9%
and -36.1%, respectively (p<0.01). Furthermore, the co-administration
was more effective than ezetimibe monotherapy, with the mean change in
direct LDL from baseline of -49.9% and -18.1%, respectively (p<0.01).
At the treatment endpoint, 77% (207/268) of the ezetimibe/simvastatin-treated
patients were below the NCEP ATP III Guidelines target LDL levels as compared
to 64% (167/261) of the simvastatin monotherapy-treated patients. Overall,
when ezetimibe was added to simvastatin, there was an additional 13.8%
decrease in LDL. Ezetimibe was also well tolerated. There was no incidence
of elevated AST, ALT, or CPK reported. Two patients in the simvastatin
monotherapy-treated group (on 20- and 40-mg doses) had elevations in CPK > 10 times the upper limit of normal (n=1 with associated muscle
symptoms). Asymptomatic elevations of AST and ALT were seen in eight patients
(n=6 co-administration arm and n=2 simvastatin monotherapy). The authors
concluded that ezetimibe was well tolerated and possesses a safety profile
similar to simvastatin and placebo.

Adverse Drug Reactions

Overall, ezetimibe is well tolerated. When used
as monotherapy, the most commonly reported adverse effect is back pain
(4.1%). In the majority of the studies, the adverse effects associated
with ezetimibe were similar to placebo. Additionally, when it is used
in combination with a statin, ezetimibe has a side effect profile similar
to statin monotherapy. When ezetimibe was administered with a statin,
there was a slight increase in the incidence of elevated transaminases
compared to statin monotherapy.

Drug-Drug Interactions

Ezetimibe does not appear to affect the absorption
of triglycerides or fat-soluble vitamins. It is not a substrate for the
cytochrome (CY) P450 1A2, 2D6, 2C8/9, or 3A4, and has not been shown to
induce or inhibit any of the CYP450 enzymes. Additionally, ezetimibe has
no interaction with common medications that are metabolized via the CYP450
system [e.g., warfarin (Coumadin®), digoxin (Lanoxin®), cimetidine
(Tagamet®), glipizide (Glucotrol®)]. It also does not have an
effect on the statin bioavailability. Since cholestyramine (Questran®)
decreases the area-under-the-curve (AUC) of ezetimibe by 80%, it is recommended
to administer ezetimibe 2 hours before or 4 hours after the bile-acid
binding resin. Finally, cyclosporine (Neoral®; Sandimmune®) and
gemfibrozil (Lopid®)) may increase ezetimibe concentrations and close
monitoring is recommended.

Pregnancy and Lactation

Ezetimibe is classified as pregnancy-risk category
C which is defined as either studies in animals have revealed adverse
effects on the fetus (teratogenic or embryocidal effects or other) and
there are no controlled studies in women, or studies in women and animals
are not available. Therefore, drugs should be given only if the potential
benefits justify the potential risk to the fetus. Ezetimibe has been studied
in pregnant rabbits and rats, but there is no adequate data for use in
pregnant women. It has also been studied in nursing rats, but it is not
known whether ezetimibe is excreted into human breast milk. Therefore,
ezetimibe should not be used in nursing mothers unless the benefit clearly
outweighs the risk.

Monitoring Parameters

As stated previously, the adverse effects associated
with ezetimibe are minimal. However, when used in combination with a statin,
the incidence of elevated liver function tests (LFTs) may increase slightly.
Therefore, when using ezetimibe with a statin, LFTs should be performed
at the initiation of therapy and then as recommended for the statins.
According to the NCEP ATP III Guidelines for monitoring statins, 1) baseline
measurements should include LFTs (e.g., AST and ALT) and a CPK, 2) follow-up
appointments should evaluate muscle symptoms and CPK, and 3) AST and ALT
should be evaluated 12 weeks after initiation of therapy and then, annually,
or more frequently, if needed. A cholesterol panel should be drawn to
monitor the effectiveness of ezetimibe therapy.

Dosage and Administration

Ezetimibe is commercially available as 10
mg tablets. The recommended dose of ezetimibe is 10 mg administered by
mouth once daily. It may be taken with or without food, and when using
ezetimibe as an adjunct to statin therapy, it may be taken at the same
time as the statin. The Average Wholesale Price (AWP) for 10 mg ezetimibe
is $2.35 for each tablet, while 30 tablets is $70.64.

Summary

Ezetimibe is a therapeutically beneficial drug that works by a unique
mechanism and differs from traditional lipid lowering therapies. Ezetimibe
may be used alone or in combination with statins for lowering lipids.
However, statins as monotherapy are more effective in lowering lipid levels
than ezetimibe monotherapy. As monotherapy, ezetimibe is well tolerated
having adverse effects similar to those seen with placebo. It is well
known that the adverse effects associated with statins, such as myopathy,
rhabdomyolysis and elevated LFTs are dose dependent. Ezetimibe may be
used with a statin to increase lipid lowering without increasing the chance
for adverse effects.